TW200522943A - Fine crystallites and a pharmaceutical composition comprising them - Google Patents

Abstract

This invention provides a fine crystallites of, , (S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide with below 80 μm of average size of particles and a pharmaceutical preparation comprising them.

Description

200522943 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to (S)-(+) -3,3,3 -trifluoro-2 · hydroxy-2-methyl-N- (5,5 , 10-trioxo-4,10-dihydrothieno [3,2 meaning; 1 [1] benzothiohex-9-yl) crystals of propanefluoride [hereinafter referred to as compound (I)] and containing the same Crystallized pharmaceutical preparation. [Prior art] Compound (I) is effective in treating various diseases or symptoms such as frequent urination, urinary incontinence, and overactive wrists. Its crystallization and synthesis methods are known, and examples of its use patterns are also clear (for example, refer to W098 / 46587, W002 / 78710, WO02 / 78711, WO02 / 7 87 1 2. JP 2002- 5 35 80). The compound (I) obtained by the method described in the literature has a plate-like crystal having a crystal average particle diameter of 100 to several hundreds / m, and has low solubility in water and oral absorption. In addition, the crystallization of the compound (ί) has no stable properties in the dissolution, absorption, and stability properties in the formulation engineering. Even if the solution can improve its absorption, the stability is still low. [Summary of the Invention] The object of the present invention is to provide crystals of the compound (I) having excellent solubility, absorption, stability, and the like, and pharmaceutical preparations containing the crystals. The present invention relates to the following (1) to (9). (1) A fine crystal, characterized by an average particle diameter of 80 V m or less, as follows: 200522943

(S)-(+) -3,3,3 · trifluoro-2 -hydroxy-2-methyl-N- (5,5,10-trioxo-4,10-dihydrothieno [ 3,2 <] [1] Fine crystals of benzothion-9-yl) propanamide. (2) The fine crystal according to item (1) above, wherein (S)-(+) -3,3,3-trifluoro-2-hydroxy-2-methyl-N · (5,5,10 · The average particle diameter of the fine crystals of trioxo-4,10-dihydrothieno [3,2_c] [l] benzothiazepine-9-yl) propanamide is 1 to 40 μm. (3) As in (S)-(+) -3,3,3-trifluoro-2-hydroxy-2-methyl-N- (5,5,10- Trioxo-seven: ^-dihydrothieno ^^ ": ^^ benzothiohex-9-yl) propanefluoride fine crystals, in which the degree of crystallinity is 15% or more. (4) As described in (1) above ) Or (2) of (S)-(+) -3,3,3-trifluoro-2-hydroxy-2-methyl-N · (5,5,10-trioxo-4,10-di Fine crystals of hydrothieno [3,2-c] [l] benzothih-9-yl) propanefluoride, in which the crystallinity is 25% or more. (5) As described in (1) or (2) above (S) · (+) · 3,3,3-trifluoro · 2-hydroxy-2-methyl (5,5,10 · trioxo-4,10-dihydrothieno [3,2- 〇] [1] Fine crystals of benzothion-9-yl) propanamine, in which the crystallinity is 45% or more. 0 200522943 (6) As (S) in item (1) or (2) above -(+) -3,3,3-trifluoro- 2-meryl-2-methyl-^ [-(5,5,10-trioxo-4,10-dihydrothieno [3,2- (:] [1] Fine crystals of benzothiu-9-yl) propanamide, wherein the degree of crystallinity is more than 75%. (7) A pharmaceutical preparation, characterized in that it contains the above-mentioned (1) ~ ( 6) Fine crystals according to any one of the items (8)-species The method for producing fine crystals according to any one of the items (1) to (6), which is characterized by including (S)-(+) -3,3,3-three having an average particle diameter of 80 // m or more Fluoro-2-hydroxy-2-methyl-^ (5,5,10-trioxo-4,10-dihydrothieno [3,2-c] [l] benzothion-9-yl) propane The process of dry pulverization of amidine. (9) The method for producing fine crystals according to the above item (8), wherein a jet pulverizer is used in the pulverization process. In this detailed description, "(S)-(+) -3, 3,3-trifluoro-2-hydroxy-2-methyl · N- (5,5,10-trioxo-fluorene, ^ -dihydrothieno ^ synthyl ^ benzothion-9-yl "Propanamide" ("Compound (I)") means an amorphous compound (I), a crystalline compound (I), or a mixture of the two. The crystallinity and average of "Compound (I)" used as a raw material The particle diameter and the like are not limited. "(S)-(+)-3 3 3 difluoro-2-hydroxy-2 · methyl-N- (5, 5 ", 10-trioxo-4,10-dihydrothieno [3,2-c] [l] benzothih-9-yl) propanamidine" ("fine crystals of compound (I)") means Average particle diameter is 8 The crystalline compound (I) from 0 to m is not particularly limited, but is preferably a fine crystal having an average particle diameter of 1 to 3 mm. It is more preferable to use "fine crystals of compounds" with a crystallinity of 15% or more. Among them, "fine crystals of compounds (industry) 200522943" with a crystallinity of 25% or more is better, and a crystallinity of 45% or more "Fine crystals of compound (I)" is more suitable, and "fine crystals of compound (I)" having a crystallinity of 75% or more is more preferable.

The method for preparing the "fine crystals of the compound (I)" in the present invention is not particularly limited. For example, the "average particle" prepared by a method such as W098 / 465 87, JP 2002-5 35 80, or a method based thereon is used. (S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N- (5,5,10-trioxy · 4,1 (κ Crystals of dihydrothieno [3,2-c] [l] benzothih-9-yl) propanamide "(" crystals of compound (I) ") can be prepared by crushing and / or screening The combination of pulverization and / or sieving is appropriate for several times. It can be pulverized using a general pulverizer, but dry pulverization is particularly preferred. Dry pulverization refers to a method for pulverizing solids in air. A mortar and machinery can be used As the above-mentioned pulverizer, a pulverizer, a jet pulverizer, or the like can be prepared to have a desired average particle diameter or average by appropriately adjusting the rotation speed of the pulverizer, the supply speed of "crystallization of the compound (I)", and the pulverization time. "Fine crystals of compound (I)" of particle diameter and crystallinity. Among them, the pulverization by a jet mill is more preferable, for example, " The "crystal of compound (I)" can be pulverized under the conditions of a feed rate of 0.1 to 1000 g / min and a pulverization pressure of 0.01 to 1.0 MPa. The "crystal of compound (I)" The "fine crystal" pharmaceutical preparation may be any type of pharmaceutical preparation containing the above-mentioned "fine crystal of compound (I)", for example, (a) "fine crystal of compound (I)" prepared by the above-mentioned method and additives The formulator, (b) mixed the "fine crystals of compound (I)" and additives prepared by the method described above, and crushed and / or sieved the mixture by the method of preparing the "fine crystals of compound (I)" 200522943 (C) The "compound (I)" and the dispersant are prepared into a solid dispersion, and the solid dispersion and additives are mixed to prepare a solid dispersion. The "compound" in the pharmaceutical preparation of the present invention The content of (I) fine crystals is preferably 0.001 to 80%, and more preferably 0.1 to 50%. This solid dispersion system consists of "compound (I)" or "compound (I)"

"Crystalline" and a solid dispersion prepared by dispersing the former dispersant. The crystalline portion of compound (I) in this solid dispersion is the average particle diameter or average particle size of the "fine crystal of compound (I)". The diameter and crystallinity are not particularly limited. More suitable dispersants include polymers such as hydroxypropyl methylcellulose (HPMC), polypropylene pyrrolidone (PVP), and hydroxypropyl cellulose (HPC). The compounding ratio of the "compound (I)" or "crystal of the compound (I)" and the dispersant is preferably 1: 0 · 1 to 1: 1 0 (weight ratio), of which 1: 0 · 1 to 1: 4 (weight ratio) is more appropriate. The method for preparing this solid dispersion is also not particularly limited, for example, "Compound (I)" or "Compound (I)" prepared by a method such as W09 8/465 87, JP 2002-5 3 5 80, or the like. The crystallization of I) and the dispersant are prepared by a method generally adopted such as a mixing pulverization method and a solvent method. In the mixing and pulverizing method, for example, a method of mixing "crystals of the compound (I)" with a dispersant using a mixing machine, and then pulverizing with a commonly used pulverizer such as a mortar, a mechanical pulverizer, a jet pulverizer, etc. By appropriately adjusting the rotation speed of the pulverizer, the supply speed of the "crystal of the compound (I)", the pulverization time, etc., it is possible to obtain fine "compound (I)" containing the desired average particle diameter or average particle diameter and crystallinity. "Crystal" and a solid dispersion of dispersant. Among them, pulverization by a jet pulverizer is preferable. The solvent method, for example, makes the "Compound (I)" or "Compound (I)"

The "crystal" and the dispersant are dissolved or dispersed in an organic solvent together, and then the organic solvent is removed by a conventional method under reduced pressure or normal pressure. Specifically, for example, a fluidized bed granulation device, an agitation granulation device, a spray granulation device, a spray drying granulation device, a vacuum drying granulation device, and the like, and a commonly used pulverizer such as a mortar, a mechanical pulverizer, and a jet A combination of pulverizing methods such as a pulverizer. As for the organic solvent, as long as it can dissolve "the compound (I)" or "the crystal of the compound (I)", there is no particular limitation, such as halogenated hydrocarbons such as dichloromethane, dichloroethane, and trichloromethane, and acetone. Ketones such as methyl ethyl ketone; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran; esters such as ethyl acetate; Additives such as an excipient, a binder, a disintegrant, a lubricant, a plasticizer, a surfactant, a coating agent, a colorant, a flavoring agent, an acidulant, and the like can be appropriately selected depending on the type of the preparation. Examples of the excipient include sugars such as sugar, mannitol, and lactose; starches such as corn starch and potato starch; and celluloses such as crystalline cellulose. Binders such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin, methyl cellulose

Vitamins, ethyl cellulose, polyvinylpyrrolidone, etc. Examples of disintegrating agents include starches such as corn starch and potato starch, crystalline cellulose, and crospovidone. Lubricants such as magnesium stearate, talc and the like. Plasticizers such as vegetable oil, glycerin, and the like. Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, fatty acid esters, and the like. Coating agents are, for example, sugar, hydroxypropyl cellulose, and the like. Colorants such as food coloring, tar pigments, etc., flavoring agents such as saccharin -10- 200522943, sodium, aspartame, stevia, etc., and acidulants such as citric acid, malic acid, tartaric acid and the like. "(S)-(+) -3,3,3-trifluoro-2-hydroxy-2-methyl-N- (5,5,10-trioxo-4,1〇 with a crystallinity of 15% or more -Crystallization of dihydrothieno [3,2 <] [1] benzothiazol-9-yl) propanamidamine "(" the crystal of compound (I) with a degree of crystallinity of more than 5% ") as long as it is a crystal The crystalline compound (I) having a degree of crystallinity of 15% or more is not particularly limited. Among them, a crystalline compound (I) having a crystallinity of 25% or more is preferable, and a crystal having a crystallinity of 45% or more is preferable. The crystalline compound (I) is more suitable, and among them, the crystalline compound (I) having a crystallinity of 75% or more is most preferable. There is no particular limitation on the production method. For example, it can be produced by a method such as WO 98/46587, JP 2002-5 3 5 80, or a method based on this. The pharmaceutical preparation containing the "crystal of the compound (I) having a crystallinity of 15% or more" may be any pharmaceutical preparation containing the aforementioned "crystal of the compound (I) having a crystallinity of 15% or more". The preparation method of the preparation is also not particularly limited. For example, a preparation method of a pharmaceutical preparation containing the "fine crystals of the compound (I)" can be used. In addition, a solid dispersion system containing "the crystal of the compound (I) having a degree of crystallinity of 15% or more" and a dispersant "compound (I)" or "crystal of the compound (I)" and a dispersant capable of dispersing the former A solid dispersion, as long as the crystal portion of the compound (I) in the solid dispersion has a crystallinity of 15% or more, the average particle diameter is not particularly limited, and the method for producing the solid dispersion is also not particularly limited. For example, the same method as the method for producing a solid dispersion containing the "fine crystals of the compound (I)" and a dispersant can be used. More suitable dispersants include HPMC, PVP, HPC and the like. In addition, the blending ratio of 200522943 "compound (η" or "crystal of compound (i)") and the dispersant is preferably 1: 0.1 to 1:10 (weight ratio), of which 1: 0.1 to 1: 4 ( The weight ratio) is more suitable. The formulation type of the pharmaceutical preparation of the present invention, for example, dragees such as sugar-coated tablets, powders, granules, capsules, nine-dose, tablets, suspension liquids, etc., is commonly used according to the technical field of formulation. The above preparations can be prepared by mixing engineering, pulverizing engineering, sieving engineering, granulating processing engineering, granulating processing engineering, ingoting engineering, drying engineering, capsule filling engineering, coating engineering and other preparation engineering. The following examples are used as examples. The present invention will be described more specifically with comparative examples and test examples, but the present invention is not limited to these examples, comparative examples, and test examples. [Embodiment] Example 1 will be prepared by the method described in JP-A-2002-35358. The crystals of the unpulverized compound (I) were obtained and pulverized using a jet pulverizer (A-0 jet / Nishikin Co., Ltd.) under conditions of a pulverizing pressure of 0,4 MPa and a supply rate of lg / min. Using a laser light scattering particle size distribution measurement Hold (LDSA-1 300A / Tohnichi Computer Application) The average particle diameter of the compound (I) before and after pulverization was measured. The crystallinity of the compound (I) before and after pulverization was measured using an X-ray diffraction apparatus (PW3050 / PANalytical). Results As shown in Table 1. Table 1 Average particle diameter crystallinity after pulverization before crushing Average particle diameter crystallinity 9 0 // m 90¾ 5 μm 80 ° / 〇 Example 2 200522943 Use the method described in JP 2002-5 3 5 80 The crystals of the uncomminuted compound (I) were cooled with ice cubes, and then pulverized using a jet pulverizer under the conditions of a pulverization pressure of 0.6 MPa and a supply rate of 2 kg / hour. A laser light scattering particle size distribution measuring device (Mastersizer 2) was used. 0 0 0 / Malbon Instruments) The average particle diameter of the compound (Π) before and after pulverization was measured. The crystallinity of the compound (I) before and after pulverization was measured using an X-ray diffraction apparatus (PW3050 / PANalytical). The results are shown in Table 2 Table 2 Crushing 丄! Ϋ Crushing average particle size crystallinity average particle diameter crystallinity 90 // m 90% 1 0 // m 80%

Example 3 0.8 g of the pulverized compound (I) prepared in Example 2 and 3.2 g of hydroxypropyl methyl cellulose were mixed in a plastic bag to obtain compound (I) and hydroxypropyl methyl cellulose. mixture. Example 4 The unpulverized compound (I) prepared by the method described in JP 2 0 2-5 3 5 8 0, 7 g of it was taken out as a test article, and each was performed using an automatic mortar (ANM1000 / nit). Crush for hours, 4 hours and 24 hours. The average particle diameter of the compound (I) before and after pulverization was measured using a laser light scattering type particle size distribution measuring device (LDSA-1 300A / Tohnichi Computer Application). The results are shown in Table 3. Table 3 Milling time 1 hour, 4 hours, and 24 hours before crushing Average particle diameter (// m) 90 11 4 4 -13- 200522943 Example 5 Unmilled compound (I) prepared by the method described in JP 2002-535 80 'Remove 4 g of them as a test article, and use an automatic mortar (ANM1000 / nit) to pulverize for 1 hour and 4 hours, respectively. The crystallinity of the compound (j) before and after the pulverization was measured using a X-ray diffraction device (PW3050 / PANalytical). The results are shown in Table 4. Table 4 Crushing time 1 hour 4 hours before crushing Crystallinity (%) 90 49 29 Example 6 0 · 8 g of compound 5 obtained in Example 5 was crushed in a mortar for 1 hour and 3 · 2 g of propyl formamide The base cellulose is mixed in a plastic bag to obtain a mixture of the compound (j) and hydroxypropylmethyl cellulose. Example 7 The compound (I) prepared in Example 5 after being crushed in a mortar for 4 hours and 3.2 g of hydroxypropylmethyl cellulose were mixed in a plastic bag to obtain compound (J) and hydroxypropyl. A mixture of methyl cellulose. Example 8 The spray-milled compound (I) obtained in Example 1 was dispersed in a 0.5% methyl cellulose aqueous solution, and an amount equivalent to 25 mg of the compound (I) was filled in a capsule to obtain a capsule. Example 9 The compound (I) prepared in Example 4 after being crushed in a mortar for 24 hours was dispersed in a 0.5% methylcellulose aqueous solution, and a capsule containing an amount equivalent to 25 mg of the compound (I) was charged in a capsule. To obtain capsules. Example 10 25 mg of the pulverized compound (I) prepared in Example 1 was filled into capsules to obtain capsules. Example 11 1 25 mg of the pulverized compound (I) prepared in Example 1, 60 mg of lactose, 30 mg of potato starch, 2 mg of polyvinyl alcohol, 1 mg of magnesium stearate, and a small amount of tar pigment was prepared by a conventional method. Into lozenges. Comparative Example 1 The unpulverized compound (I) obtained by the method described in JP 2002-5 35 80 was dispersed in a 0.5% methyl cellulose aqueous solution, and an amount equivalent to 25 mg of the compound (I) was charged in In capsules, capsules were prepared. Comparative Example 2 Capsules were prepared by filling 25 mg of an unpulverized compound (I) obtained by the method described in JP 2002-5 35 80 into capsules. Test Example 1 The dissolution test (kneading method) of each of the colloidal agents prepared in Examples 8, 9 and Comparative Example 1 was carried out. The results are shown in Figure 1. From Figure 1, it is shown that the capsule containing the pulverized compound (I) (Example 8) and the capsule containing the pulverized compound (I) (Example 9) are smaller than the capsule containing the unpulverized compound (I) The agent (Comparative Example 1) has a high dissolution rate, and it can be seen that the dissolution characteristics can be improved by pulverizing the compound (I) to an appropriate particle diameter. Test Example 2 One capsule of each of the capsules prepared in Example 10 and Comparative Example 2 was orally administered to a dog under fasting through -15-200522943. Blood was collected over time and the concentration of compound (I) in plasma was measured by high-speed liquid chromatography (HPLC). The results are shown in FIG. 2. As shown in FIG. 2, when the capsule containing the pulverized compound (0) (Example 10) was administered, the capsule containing the unpulverized compound (Π) was administered more than the capsule (Comparative Example 2). At this time, the plasma has a higher concentration, and it can be seen that the compound (I) can be pulverized into an appropriate particle diameter to improve its oral absorption. The measurement conditions of HPLC are as follows. Analytical equipment: LC -10A series (manufactured by Shimadzu Corporation) Column: Develosil ODS-HG-5 Column temperature: room temperature mobile phase: 0.05mol / L phosphate buffer (PH3.0) / acetonitrile = 3/2 flow rate: 1mL / min detection Conditions: UV 242 nm Test Example 3 The mixtures of the compound (I) and hydroxypropyl methylcellulose prepared in Examples 3, 6 and 7 were filled into plastic bottles, and stored at 60 ° C for 10 The average particle size of the compound (I) in the mixture obtained in Example 6 and Example 7 was determined by the HPLC method. The results are shown in Example 4 where the same pulverization process was performed. It can be seen from Table 5 that any test product has high stability. 20052 2943 Table 5: Decomposition content test product Example 3 Example 6 Example 7 Crystallinity (%) 80 49 29 Average particle size (# m) 10 11 4 Decomposition content (%) 0.0 0.1 0.1 Applied to industry Possibility The present invention provides fine crystals of the compound (I) having excellent solubility, absorption, and stability, and a pharmaceutical preparation containing the fine crystals. [Simplified Description of the Drawings] Figure 1 is shown as Example 8, Example 9, and Comparison A graph of the results of the dissolution test (stirring method) of each capsule prepared in Example 1. The dissolution rate (%) of the compound (I) in the longitudinal axis capsules, the time (minutes) in the horizontal axis, and the error bar means Standard deviation.-□-: indicates the dissolution curve of the capsules [containing the pulverized compound (I)] prepared in Example 8.-◊-: indicates the capsules [containing the pulverized compound (I) in Example 9] )].-△-: It is the dissolution curve of the capsules [containing the unpulverized compound (I)] prepared in Comparative Example 1. Figure 2 shows the capsules prepared in Example 10 and Comparative Example 2. Test results of oral absorption in dogs. The concentration (%) of the compound (I) in the axis plasma, the horizontal axis time (hours), and the error bar refers to the standard deviation. I)], the concentration of the compound (I) in the plasma. -17- 200522943-•-: Expressed as the compound (I) in the plasma when using the capsules [containing the unpulverized compound (I)] prepared in Comparative Example 2 [Concentration of component symbols]

Arvr IIII-

Claims (1)

200522943 10. Scope of patent application: 1 · A fine crystal, which is characterized by an average particle diameter below 80 # m, as shown in the following formula (S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N- (5,5,10-trioxo-4,10-dihydrothieno shown Fine crystals of [3,2_c] [l] benzothiazol-9-yl) propanamide. 2. The fine crystal as described in the first item of the patent application scope, wherein (s)-(+) -3,3,3-trifluoro-2 · hydroxy-2-methyl-N- (5,5,10-tri The average particle diameter of the fine crystals of the oxygen-4,10-dihydrothieno [3,2-c] [l] benzothiohex-9-yl) propanamide is 1 to 40 // m or more. 3. If (S)-(+) -3,3,3-trifluoro-2- · hydroxy-2-methyl · N- (5,5,10 -trioxo Fine crystals of -4,10-dihydrothieno [3,2-(:] [1] benzothiazepine-9-yl) propanehydrazine, in which the degree of crystallinity is more than 15%. 4. If applying for a patent (5)-(+)-3,3,3-trifluoro-2-meryl-2-methyl-^ (5,5,10-trioxo-4,10-di) in the range 1 or 2 Hydrothieno [3,2 <] [1] benzothien-9-yl) propanefluoride fine crystals, in which the degree of crystallinity is 25% or more. 5. If the scope of patent application for item 1 or 2 (S )-(+) · 3,3,3-triple-2 · -19- 200522943 hydroxy-2-methyl-N- (5,5,10-trioxo-4,10-dihydrothieno [3 , 2-c] [1] Fine crystals of benzothion-9-yl) propanamide, in which the degree of crystallinity is more than 45%. 6. If (S)-(+ ) -3,3,3-trigas-2-hydroxy-2-methyl-N- (5,5,10 · trioxo-4,10-dihydrothieno [3,2-(:] [1 ] Fine crystals of benzothion-9-yl) propanamide, in which the degree of crystallinity is more than 75%. 7 · —A kind of medicinal preparation'characteristics include those in the scope of patent applications No. 1 to 6 Fine crystal of any one of the items. 8 · —A method of producing fine crystal according to any one of the items 1 to 6 of the scope of patent application ', which is characterized by (S)-including an average particle diameter of 8 0 // m or more (+)-3,3,3-Digas-2-meryl-2-methyl-] ^-(5,5,10-trioxo-4,10-dihydrothieno [3,2-cHl ] Benthionol-9-yl) propane hydrazine for dry pulverization. 9 · For example, the method for producing fine crystals in the scope of patent application No. 8, wherein a jet pulverizer is used in the pulverization process. -20-